Possible involvement of GABAergic and nitriergic systems for antianxiety-like activity of piperine in unstressed and stressed mice

BackgroundAn investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine.MethodsPiperine (5, 10 and 20 mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6 h. Antianxiety activity was evaluated by employing elevated plus maze, light–dark box and social interaction test. Diazepam was employed as standard anxiolytic drug.ResultsPiperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50 mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20 mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice.ConclusionThese data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.     

HPLC测定赤胫散中的3,3’-二甲基鞣花酸和3,3’,4’-三甲基鞣花酸

目的采用HPLC测定赤胫散中的3,3’-二甲基鞣花酸和3,3’,4’-三甲基鞣花酸。方法色谱柱为Dikma-C18柱,流动相为甲醇-乙腈-0.1%磷酸(17∶33∶50),流速1 m L·min-1,检测波长248 nm,柱温30℃。结果 3,3’-二甲基鞣花酸0.198~0.990μg(r=0.9991)、3,3’,4’-三甲基鞣花酸0.098~0.491μg(r=0.9990)与峰面积的线性关系良好,回收率分别为102.40%、98.41%,RSD分别为2.25%、1.87%(n=6)。结论所用方法简便、快捷、准确,可用于赤胫散药材的质量控制。     

RP-HPLC法测定开西尼孜散剂中没食子酸和鞣花酸的含量

目的建立同时测定开西尼孜散剂中没食子酸和鞣花酸含量的RP-HPLC方法。方法色谱柱为Waters X-Bridge C18(250mm×4.6mm,5μm);流动相为甲醇-乙腈-2 mL·L-1磷酸水溶液,梯度洗脱;流速为1.0 mL·min-1;检测波长为254nm。结果没食子酸和鞣花酸的线性范围分别为0.132~0.792μg(r=0.999 9)和0.108~0.648 2μg(r=0.999 9),平均加样回收率分别为99.3%和98.8%,方法精密度RSD分别为1.4%和1.7%(n=6)。结论该方法操作简便、快速、准确、灵敏度高、重复性好,可为开西尼孜散剂质量评价提供实验依据。     

高效液相色谱法测定地锦草中鞣花酸的含量

目的建立地锦草中鞣花酸含量的测定方法。方法采用高效液相色谱法,色谱柱：OdyssilC18（4.6 mm×250 mm,5μm）;流动相：甲醇-0.1%磷酸（40：60）;流速：1.0 mL·min^-1;检测波长：254 nm;柱温：30℃。结果鞣花酸进样量在0.032～0.476μg与峰面积呈良好的线性关系,r=0.999 9,平均加样回收率为97.3%,RSD为1.4%。结论该方法简便准确,重现性好,可作为地锦草中鞣花酸的含量测定方法。     

Potential roles of ellagic acid on metabolic variables in diabetes mellitus: A systematic review

Diabetes mellitus is a widespread endocrine disorder globally. Due to its antioxidant and anti-inflammatory properties, ellagic acid has the potential to improve the metabolic effects of chronic non-communicable diseases. This systematic review summarizes current evidence about the potential effects of ellagic acid on metabolic variables in diabetes mellitus. A comprehensive systematic literature search was conducted in databases such as PubMed, Scopus, EMBASE, ProQuest and Google Scholar from inception until March 2022. All animal studies and clinical trials were eligible for inclusion. Studies using in vitro models or published in a non-English language were excluded. Of 1320 articles, 23 were selected for assessment, including 21 animal studies and two randomized controlled trial studies. Following ellagic acid administration, findings reported improvement in FBS, HbA1c, insulin (20, 8 and 12 studies, respectively), TG, TC, HDL-C (13, 10 and 5 studies, respectively), MDA, GSH, CAT, SOD (11, 6, 3 and 4 studies, respectively), and TNF-α and IL-6 (6 and 3 studies, respectively). In conclusion, ellagic acid may improve glycaemic indicators, dyslipidaemia, oxidative stress and inflammation in diabetes mellitus. However, further clinical trials are needed to explore the mechanisms more precisely and to observe the applied consequences.     

鞣花酸壳聚糖-海藻酸钠微球的制备工艺

目的:优化鞣花酸壳聚糖-海藻酸钠微球的最佳制备工艺。方法:采用一步法,以壳聚糖-海藻酸钠作为载体材料制备鞣花酸微球,并以微球载药量和包封率为考察指标,通过单因素筛选及正交设计优化出鞣花酸壳聚糖-海藻酸钠微球的制备工艺。用溶出仪在900 ml释放介质(pH 6.86)和120 r·min^-1转速条件下测定释放度。结果:优化工艺为海藻酸钠与药物比为3:1,氯化钙质量分数为2%,海藻酸钠质量分数为2%,壳聚糖质量分数为0.1%,温度为60℃,pH为5,所得鞣花酸平均粒径为(980±100)μm,平均载药量为27.22%,平均包封率为97.73%,48 h释放度为74.22%。结论:本制备工艺稳定,操作简便,重现性好,可用于鞣花酸壳聚糖-海藻酸钠微球的制备。     

Significant elevation of antiviral activity of strictinin from Pu’er tea after thermal degradation to ellagic acid and gallic acid

Compared with abundant catechins, strictinin is a minor constituent in teas and has been demonstrated to possess inhibitory potency on influenza virus. In this study, strictinin was found as the major phenolic compound in Pu’er teas produced from leaves and buds of wild trees. Due to its thermal instability, strictinin, in tea infusion or in an isolated form, was completely decomposed to ellagic acid and gallic acid after being autoclaved for 7 minutes. A plaque reduction assay was employed to compare the relative inhibitory potency between strictinin and its thermally degraded products against human influenza virus A/ Puerto Rico/8/34. The results showed that the antiviral activity of ellagic acid regardless of the presence or absence of gallic acid was significantly higher than that of strictinin. Thermal degradation of strictinin to ellagic acid and gallic acid seems to be beneficial for the preparation of Pu’er teas in terms of enhancing antiviral activity.     

Antidepressant-like effects of triiodothyroacetic acid in mice

Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity andl-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.     

石榴叶提取物中鞣花酸在大鼠体内药物动力学研究

目的通过大鼠口服石榴叶提取物,研究其中活性成分鞣花酸的药动学特征。方法采用反相HPLC法,紫外检测,应用药动学软件3p87拟合大鼠体内鞣花酸的药动学模型。结果鞣花酸在大鼠体内呈二室模型分布,主要药动学参数为:α=1.07h-1,β=0.12h-1,Ka=5.67h-1,t1/2α=0.65h;t1/2β=5.94h;t1/2Ka=0.12h;K21=0.36h-1;K10=0.35h-1;K12=0.48h-1;AUC=0.85g·h·L-1。结论鞣花酸药动学特征为口服血药浓度低,大部分经胃吸收,达峰时间短,快速吸收、快速分布消除。石榴叶中鞣花酸的吸收大于鞣花酸单体的吸收。     

鞣花酸对D-型半乳糖致衰老大鼠干预的尿液代谢组学生物标志物的筛选及代谢通路分析

目的：利用高效液相色谱串联质谱仪（LC-MS）的尿液代谢组学方法,考察鞣花酸对D-型半乳糖致衰老大鼠内源性物质代谢的影响,寻找潜在的生物标志物并分析代谢途径,为研究鞣花酸对D-型半乳糖致衰老大鼠的改善作用及其机制提供理论依据。方法：采用皮下颈静脉注射D-型半乳糖的方法建立氧化衰老大鼠模型,灌胃给予鞣花酸连续8周,收集给药8周24 h尿液,用液相色谱--高分辨质谱对其检测分析;采用主成份分析（PCA）、偏最小二乘法判别分析（PLS-DA）及正交偏最小二乘法判别分析（OPLS-DA）等方法对正常对照组,模型组,阳性对照组,鞣花酸高剂量组、中剂量组、低剂量组6组大鼠尿液代谢物进行聚类分析,筛选出潜在的生物标志物并构建相应的代谢通路。结果：代谢组学分析发现造模后第8周各组大鼠尿液有明显的聚类现象,通过对重要变量的分析鉴定,筛选出12个潜在的生物标志物;涉及的代谢通路包括三羧酸循环、色氨酸代谢、丙酮酸代谢、二元羧酸及牛磺酸代谢等。结论：鞣花酸干预下的D-型半乳糖致衰老大鼠内源性代谢物聚类性趋近正常水平,为进一步阐明鞣花酸对D-型半乳糖致衰老大鼠的作用机制提供依据。     

Preparation method and stability of ellagic acid-rich pomegranate fruit peel extract

A simple one-step purification using liquid–liquid extraction for preparing pomegranate peel extract rich in ellagic acid has been demonstrated. The method involved partitioning of the 10% v/v water in methanol extract of pomegranate peel between ethyl acetate and 2% aqueous acetic acid. This method was capable of increasing the ellagic acid content of the extract from 7.06% to 13.63% w/w. Moreover, the antioxidant activity of the extract evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay was also increased (ED₅₀ from 38.21 to 14.91?μg/mL). Stability evaluations of the ellagic acid-rich pomegranate peel extract in several conditions through a period of four months found that the extracts were stable either kept under light or protected from light. The extracts were also stable under 4° ± 2°C, 30° ± 2°C and accelerated conditions at 45°C with 75% relative humidity. However, study on the effect of pH on stability of the extract in the form of solution revealed that the extract was not stable in all tested pH (5.5, 7 and 8). These results indicated that the ellagic acid-rich pomegranate peel extract was stable when it was kept as dried powder, but it was not stable in any aqueous solution.     

The anti-tumourigenic effect of ellagic acid in SKOV-3 ovarian cancer cells entails activation of autophagy mediated by inhibiting Akt and activating AMPK

This study investigated the effect of ellagic acid (EA) on SKOV-3 cell growth and invasiveness and tested if the underlying mechanism involves modulating autophagy. Cells were treated with EA in the presence or absence of chloroquine (CQ), an autophagy inhibitor, compound C (CC), an AMPK inhibitor, or an insulin-like growth factor-1 (IGF-1), a PI3K/Akt activator. EA, at an IC₅₀ of 36.6 µmol/L, inhibited cell proliferation, migration, and invasion and induced cell apoptosis in SKOV-3 cells. These events were prevented by CQ. Also, EA increased levels of Beclin-1, ATG-5, LC3I/II, Bax, cleaved caspase-3/8 and reduced those of p62 and Bcl-2 in these cancer cells. Mechanistically, EA decreased levels of p-S6K1 (Thr³⁸⁹) and 4EBP-1 (Thr^37/46), two downstream targets of mTORC1, and p-Akt (Thr³⁰⁸) but increased levels of AMPK (Thr¹⁷²) and p-raptor (Ser⁷⁹²), a natural inhibitor of mTORC1. CC or IGF-1 alone partially prevented the effect of EA on cell survival, cell invasions, and levels of LDH, Beclin-1, and cleaved caspase-3. In conclusion, EA can inhibit SKOV-3 growth, migration, and invasion by activating cytotoxic autophagy mediated by inhibition of mTORC1 and Akt and activation of AMPK.     

积雪草总三萜酸及其主要成分的抗抑郁活性研究

目的:探讨积雪草总三萜酸和其主要成分积雪草酸、羟基积雪草酸的抗抑郁作用.方法:采用小鼠强迫游泳实验、小鼠悬尾实验、开野实验和拮抗利血平所致的小鼠眼睑下垂实验,分别以小鼠不动时间、自主活动数和拮抗率作为评价指标.结果:在强迫游泳实验中积雪草总三萜酸、积雪草酸、羟基积雪草酸60 mg/kg、120 mg/kg剂量均能显著缩短小鼠不动时间,在悬尾实验中30 mg/kg、60 mg/kg、120 mg/kg剂量均能显著缩短小鼠不动时间,开野实验结果表明给药后小鼠的自主活动无明显变化,在利血平拮抗实验中积雪草总三萜酸、积雪草酸、羟基积雪草酸均可减少小鼠眼睑下垂.结论:积雪草总三萜酸、积雪草酸、羟基积雪草酸有抗抑郁作用.     

Ellagic acid attenuates beryllium sulphate-induced oxidative stress and histopathological alterations of spleen in rats

ContextEllagic acid (EA) is a phenolic constituent in certain fruits and has largely been recognized for its role as an antioxidant compound.ObjectiveTo evaluate the effect of EA on beryllium sulphate-induced splenic toxicity in rats.Materials and methodsMale Sprague-Dawley rats were divided into four groups. The first group was used as control. Group 2 was exposed to BeSO₄ (12 mg/kg, b.w.). Groups 3 and 4 were treated with EA (100 and 300 mg/kg, b.w.) daily for 6 weeks after exposing to BeSO₄ (12 mg/kg, b.w.). Various biochemical and molecular biomarkers were assessed in blood and spleen.ResultsBeSO₄-intoxicated rats showed significant higher WBC (6.74 ± 0.20 × 10⁹/L vs. 11.02 ± 1.31 × 10⁹/L, p < 0.05), Neu (1.14 ± 0.11 × 10⁹/L vs. 2.45 ± 0.42 × 10⁹/L, p < 0.05), Lym (3.80 ± 0.83 × 10⁹/L vs. 9.64 ± 1.99 × 10⁹/L, p < 0.05), and PLT (868.4 ± 43.2 × 10⁹/L vs. 1408 ± 77.57 × 10⁹/L, p < 0.05) than normal control animals. Moreover, an increase in MDA with depletion of GSH and SOD activity (all p < 0.05) occurred in the spleen of rats treated with BeSO₄. Furthermore, BeSO₄-treated rats displayed significantly higher levels of apoptotic markers (Bax, Caspase-3, PARP) (all p < 0.05). EA administration resulted in a significant reversal of hematological and apoptotic markers in beryllium sulphate-intoxicated rats.Discussion and conclusionsOur results suggest EA treatment exerts a significant protective effect on BeSO₄-induced splenic toxicity in rats.     

鞣花酸体外抗真菌活性及对小鼠白色念珠菌感染模型的治疗作用研究

目的研究鞣花酸体内外抗真菌作用,确定其抗真菌谱,评价其对小鼠白色念珠菌感染的治疗作用。方法根据美国临床实验室标准化委员会(NCCLS)推荐的《酵母菌的液基稀释法抗真菌药物敏感性试验方案》(M27-A),测定鞣花酸对临床常见念珠菌的MIC值,确定其抗真菌谱,筛选出对其敏感的真菌菌株;采用小鼠腹腔注射白色念珠菌造成系统性真菌感染模型,以小鼠存活率、血清SOD和MDA含量、肝脏组织病理学为评价指标,观察鞣花酸的体内抗真菌作用。结果鞣花酸体外对念珠菌中白色念珠菌(C.albicans)最敏感,平均MIC为25.0 mg·L~(-1);与模型组比较,鞣花酸体内可明显改善造模小鼠的一般症状,使动物体重明显增加(P<0.05),高剂量组丙二醛(MDA)含量降低(P<0.05),超氧化物歧化酶(SOD)活力增加(P<0.01),肝脏组织病理学有明显改善。结论鞣花酸有明显的体内外抗真菌活性,具有一定开发利用价值。     

Antidepressant-like activity of the phenylpiperazine pyrrolidin-2-one derivatives in mice

The present study was designed to investigate the central nervous system activity of 23 novel phenylpiperazine pyrrolidin-2-one derivatives. These compounds had marked antiarrhythmic and hypotensive activities and revealed affinity for α1- and α2-adrenoceptors. These effects may be related to their α-adrenolytic properties. We assessed their antidepressant-like effect in the forced swimming test, influence of spontaneous locomotor activities and binding to 5-HT1A and 5-HT2 receptors. Our study demonstrated the strong antidepressant-like activity of compound EP-65 in the forced swimming test. The effect of EP-65 was stronger than results obtained with the classical antidepressants imipramine and mianserin. Other compounds, EP-41, EP-42, EP-44, EP-47, EP-48, EP-49, EP-50, EP-62, EP-66, EP-70, EP-75 and EP-76, showed significantly weaker activities in this test. Compound EP-42 showed the strongest affinity for 5-HT1A (Ki=24.5 nM), and compound EP-50 showed the strongest affinity for the 5-HT2 receptor (Ki=109.1 nM). All tested compounds significantly suppressed the spontaneous locomotor activity of mice. Currently, it is not possible to determine which mechanisms are involved in the witnessed antidepressant-like activity of novel phenylpiperazine pyrrolidin-2-one derivatives.     

Immunomodulating and antistress activity of ecdysterone and turkesterone under immobilization-induced stress conditions in mice

The phytoecdysteroids ecdysterone and turkesterone isolated from Rhaponticum integrifolium and Ajuga turkestanica herbs, respectively, increase the adaptation capacity of mice under immobilization-induced stress conditions. These compounds prevent involution of the thymicolymphatic system, decrease trophic disorders in gastric mucosa, prevent an increase in the weight of adrenal glands and a decrease in them of the content of ascorbic acid and cholesterol (to a much greater degree than does T-activin), and stimulate immunogenesis in animals with experimental immune deficiency developed on the background of immobilization-induced stress.     

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Aim:

To investigate the antidepressant-like effects of a novel 5-HT₃ receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods:

5-HT₃ receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5–2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5–2 mg·kg⁻¹·d⁻¹, po) or a positive drug fluoxetine (10 mg·kg⁻¹·d⁻¹, po) in the last 2 weeks, followed by behavioral and biochemical assessments.

Results:

The 5-HT₃ receptor antagonism of 6z (pA₂=7.4) in guinea pig ileum was more potent than that of a standard 5-HT₃ receptor antagonist ondansetron (pA₂=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group.

Conclusion:

6z is a novel 5-HT₃ receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.